Low-density lipoprotein receptor interacts with clusterin to regulate A1/A2 astrocyte polarization and ameliorate hemorrhagic brain injury.

BACKGROUND

Intracerebral hemorrhage (ICH) has high mortality and disability rates. Astrocytes polarize into neurotoxic A1 or neuroprotective A2 subtypes. The low-density lipoprotein receptor (LDLR) improves outcomes in neurodegenerative diseases, Single-cell sequencing analysis identifies differential Ldlr expression among subtype astrocyte post-intracerebral hemorrhage, exhibiting strong correlation with astrocyte activation. This study explores how LDLR influences astrocyte polarization and its underlying mechanism.

METHODS

Single-cell sequencing analysis assessed Ldlr expression in astrocytes and its correlation with polarization. ICH model was established in C57BL/6 J mice through stereotactic injection of autologous blood. A1 (C3+) and A2 (S100A10+) astrocytes were labeled to monitor polarization. Astrocyte-targeted adeno-associated virus (AAVs) transfection generated Ldlr knockdown mice, and mass spectrometry elucidated LDLR's molecular mechanism in astrocyte polarization and brain injury.

RESULTS

Single-cell sequencing analysis showed upregulated Ldlr in astrocyte subpopulations, linked to activation. Further experiments have shown LDLR expression increased post-ICH, peaking on day 3, and co-localized with astrocytes. Ldlr knockdown promoted A1 polarization and worsened brain injury. Mass spectrometry and co-immunoprecipitation revealed that Clusterin (CLU) is an important interacting protein. Exogenous CLU enhanced A2 polarization and improved outcomes, but this effect was abolished in Ldlr knockdown mice.

CONCLUSION

LDLR interacts with CLU post-ICH to shift astrocytes from A1 to A2, mitigating brain injury. Targeting LDLR and CLU may offer therapeutic potential for hemorrhagic brain injury.